Mortality from breast cancer is increasing in most population groups.This underlines the need for a better understanding of the etiology of the disease that could eventually lead to preventive interventions. Although several risk factors for breast cancer have been identified, it has not been possible to explain the occurrence pattern of the disease. Estrogens during adulthood remain primary candidates, but the evidence is mostly inferential and indirect; the results of most studies have been collectively suggestive but far from conclusive. The working hypothesis for the proposed study postulates that the high levels of estrogens during pregnancy increase the probability of future occurrence of breast cancer in the offspring through direct influences on the partially undifferentiated and probably highly susceptible mammary tissue of the fetus. The study will evaluate this hypothesis by comparing levels of major pregnancy estrogens between a population at high risk for breast cancer (Caucasian women in Boston) and a population at low risk for this disease (Asian and mostly rural women in Shanghai). Levels of major estrogens in the maternal blood during the 12th and 28th weeks of pregnancy will be examined in sera obtained from 300 women in each center. It is predicted that pregnancy estrogens will be higher in women at higher risk for breast cancer, i.e., women in Boston and within centers, women of higher socioeconomic class, older age, and first parity. The proposed study will also have two other objectives, as follow: (1) to identify correlates of high levels of pregnancy estrogens (e.g., birth weight, parity, maternal obesity, severe nausea during pregnancy) in order to utilize them as proxy exposure variables in studies exploring the role of prenatal exposure to endogenous estrogens in the etiology of breast cancer in humans, and (2) to identify dietary or other determinants of pregnancy estrogens, with a possible longer-term view to preventive intervention (studies assessing dietary intakes during pregnancy will be done only in Boston).